Hereditary factors play a significant role in the etiology of autism. In addition to autism, abnormalities which are milder, but qualitatively similar to behaviors which define autism (i.e., particular personality, language and cognitive characteristics, and psychiatric disorders), have been shown to aggregate in relatives of autistic individuals. Preliminary data indicate that these abnormalities may be more common and more severe in non-autistic first-degree relatives from Multiple- Incidence Autism Families (i.e., ascertained through two autistic probands) than in those ascertained through a single autistic proband, but the rate and severity of abnormalities in these two groups have not been previously compared. Clarification of the boundaries of phenotypic expression of the underlying genetic liability to autism is a critical preliminary step to further genetic analyses of this disorder. In this application, we propose to extend the research portion of the PI's Scientist Development Award for Clinicians by: 1) adding a third group of families ascertained from the population through a single autistic proband, an Autism Population Study Group (N=40), and 2) expanding the number of families in both the Multiple-Incidence Autism and Down syndrome (DS) groups from 25 to 30. The total number of families will be increased from 50 as proposed in the SDAL to 100. The aim of the SDAC, "A Family Study of Multiple-Incidence Autism Families," is: 1) to estimate the frequency of disorders that may be genetically associated with autism in first-degree relatives from Multiple-Incidence Autism and DS families and 2) to investigate the pattern of disorders among relatives that may define a lesser variant in autism. In addition to these aims, in this FIRST proposal we will compare the rate of abnormalities in first-degree relatives from: 1) Multiple- and Single-Incidence Autism Families and 2) the Autism Population and DS samples. Characteristics of the lesser variant determined from comparisons of Multiple-Incidence and DS families will then be applied to a genetic analysis of the Autism Population Sample. We also propose to study the genetic implications of elevated serotonin in autism. Previous studies suggest that peripheral serotonin may be associated with genetic liability for autism. We will further examine this association by: 1) comparing the serotonin levels in multiple- and single-incidence autistic probands and 2) exploring the relationship of serotonin levels to the presence of the lesser variant in families.